Thiazole cardiovascular agents

ABSTRACT

1-Alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanol; 5-(5-alkynylaminocarbonyl-thiazol-2-yloxymethylene)-N-alkyloxazolidine and/or 2-substituted oxazolidine derivatives thereof, and methods of making such compounds. The compounds exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The compounds are also useful in the treatment of hypertension in mammals. The 5-(5-alkynyl-aminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidines and derivatives are also intermediates for the 1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanols. The 1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanols can be prepared by base or acid hydrolysis of the corresponding 5-(5-alkynylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine or derivative; or by treatment of the corresponding 3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2,3-epoxypropane with the desired alkylamine. Similarly the 5-(5-alkynylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine or derivative can be prepared from the corresponding 1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanols via treatment with an aldehyde or ketone.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-propan-2-ol andpharmaceutically acceptable salts thereof;5-(5-alkynylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidinederivatives and pharmaceutically acceptable salts thereof and to methodof preparing such compounds. In a further aspect this invention relatesto pharmaceutical compositions comprising one or more of the abovecompounds, of the invention, and to methods of treating cardiacdisorders and hypertension in mammals.

2. The Prior Art

At the present time, the compound frequently used in the United Statesfor the treatment of several cardiac arrhythmias is propranolol (i.e.1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol). This compoundprimarily achieves its therapeutic action by blocking cardiacβ-adrenergic receptor sites and is a general β-adrenergic blocker whichblocks all β-adrenergic receptor sites including those in the lung, aswell as the β-adrenergic receptor sites in the heart. Propanolol iscontraindicated in patients who suffer from asthma or chronicobstructive lung disease, because following its administration to suchpatients, an increase in airway resistance and bronchial constrictionhas been observed. U.S. Pat. No. 3,897,441 discloses certain3-(5-substituted aminocarbonylthiazol-2-yloxy)-propan-2-ol-1-amineshaving potent β-adrenergic blocking activity and cardiac selectivity. Wehave now discovered novel analogues of this class of compounds havingunexpectedly superior β-blocking activity and/or cardiac selectivityand/or reduced cardiac depression. The compounds are especiallyfelicitous for the treatment or palliation of angina pectoris andcardiac arrhythmias and because of their cardiac selectivity can besafely applied to patients who suffer from asthma or chronic obstructivelung disease.

SUMMARY OF THE INVENTION

In summary the compounds of the invention can be represented by thefollowing generic formula: ##STR1## wherein Z has the formula:

    R.sup.1 --C.tbd.C-(CH.sub.2).sub.n --

wherein n is 2, 3 or 4; R¹ is hydrogen or an alkyl group having from onethrough four carbon atoms and wherein Z has from four through eightcarbon atoms;

Y is selected from the group having the formulas: ##STR2## wherein R²and R³ are lower alkyl; and R⁴ and R⁵ are independently hydrogen orlower alkyl.

Also encompassed within the invention are pharmaceutically acceptablesalts of the above compounds.

In summary the process of the invention for preparing the compound, ofthe invention, wherein Y is the group --CHOH--CH₂ --NHR² comprisestreating the corresponding 3-(5-substitutedthiazol-2-yloxy)-1,2-epoxypropane with an alkylamine having the desiredR² substituent. Alternatively, these compounds can be prepared,according to the invention, by hydrolysis of the corresponding compoundsof the invention, wherein Y is oxazolidine.

In summary the processes of the invention for preparing the compounds ofthe invention wherein Y is an oxazolidine group comprises condensing a2-bromo or 2-chlorothiazole having the desired 5-position substituentwith a 5-hydroxymethyl-oxazolidine having the desired R³, R⁴ and R⁵-substituents or treating the corresponding compounds of the inventionwhere Y is an alkylaminopropanol with the desired R⁴, R⁵ aldehyde orketone.

In summary the pharmaceutical compositions of the invention include bothsolutions and solids or powders comprising one or more of the compounds,of the invention, in combination with a suitable pharmaceutical solution(e.g. sterile water) or pharmaceutical solid excipients.

The invention will be further described hereinbelow.

FURTHER DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The compounds of the invention can be represented by the followingsubgeneric formulas: ##STR3## wherein R² is lower alkyl group havingfrom one through six carbon atoms and Z is a group having the formula

    R.sup.1 --C.tbd.C--(CH.sub.2).sub.n --

wherein n is 2, 3 or 4, and R¹ is hydrogen or an alkyl group having fromone through four carbon atoms and wherein the total number of carbonatoms in Z is from four through eight;

R³ is lower alkyl having one through six carbon atoms;

R⁴ and R⁵ are independently hydrogen or lower alkyl having from onethrough six carbon atoms, preferably hydrogen or methyl.

The pharmaceutically acceptable salts of the compounds of formulas IIand III are also encompassed within the invention.

The above compounds have an asymmetric carbon atom in the propoxy sidechain and hence exist as optical isomers. Further, where the R¹substituent is also dissymmetric, further optical isomers exist withrespect to this substituent. Accordingly, the above formulas areintended to represent both the respective individual isomers andmixtures thereof and the respective individual isomers as well asmixtures thereof are encompassed within the invention.

DEFINITIONS

As used hereinabove and below, the following terms shall have thefollowing meanings unless expressly states to the contrary. The termalkyl refers to both straight and branched chain alkyl groups. The termlower alkyl refers to both straight and branched chain alkyl groupshaving a total of from one through six carbon atoms and thus includesprimary, secondary, and tertiary alkyl groups. Typical lower alkylsinclude, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, n-hexyl and the like.

The term alkynyl refers to unsaturated alkyl groups having a triple bond(e.g. CH₃ C.tbd.C(CH₂)₂ --) and includes both straight and branchedchain alkynyl groups. Typical alkynyl groups include, for example,but-3-ynyl (i.e. HC.tbd.C(CH₂)₂ --); hex-4-ynyl (i.e. CH₃ C.tbd.C(CH₂)₃--); 5,5-dimethylhex-3-ynyl (i.e. ##STR4## 6-methylhept-4-ynyl (i.e.##STR5## oct-5-ynyl (i.e. C₂ H₅ C.tbd.C(CH₂)₄ --) and the like.

The term alkylamino refers to the group having the formula R'HN--wherein R' is alkyl and the term lower alkylamino refers to such groupswherein R' is lower alkyl.

The term aminocarbonyl or carbamoyl refers to the group having theformula ##STR6## The term alkynylaminocarbonyl or alkynylcarbamoylrefers to the group having the formula ##STR7## wherein R¹ and n are asdefined herein.

The term pharmaceutically acceptable salts refers to pharmaceuticallyacceptable hydrogen-anion addition salts which do not adversely affectthe pharmaceutical properties of the parent compounds. With respect tothe addition salts, suitable inorganic anions include, for example,chloride, bromide, iodide, sulfate, phosphate, nitrate, sulfate, and thelike. Suitable organic anions include, for example, acetate, benzoate,lactate, picrate, propionate, butyrate, valerate, tartrate, maleate,fumarate, citrate, succinate, tosylate, ascorbate, nicotinate, adipate,gluconate and the like.

Typical illustrations of the compounds of formula II, and salts thereof,can be had, for example, hereinbelow by reference to Examples 1-4, 7 and8. The preferred R¹ substituents are ethyl and isopropyl. The preferredR² substituent compounds of formula II are isopropyl and t-butyl andespecially isopropyl. The preferred integer n is 2, i.e. ethyl. Theparticularly preferred compounds of formula II are:

1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;and

1-t-butylamino-3-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.

Typical illustrations of the compounds of formula III can be had,hereinbelow, by reference to Examples 5, 6 and 9. The preferred R¹substituents and preferred n integers (i.e. 2) for the compounds offormula III are the same as listed above for the compounds as formulaII. The preferred R³ substituents are isopropyl and t-butyl. The simplerR⁴ and R⁵ substituents are preferred and hence the preferred compoundsof formula III are those wherein R⁴ and R⁵ are each hydrogen or eachmethyl. The particularly preferred compounds of formula III arecompounds having a preferred substituent at each of R¹, R³, R⁴ and R⁵and wherein n is 2, for example:

5-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]methylene-N-isopropyl-2,2-dimethyloxazolidine;

5-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]methylene-N-t-butyl-2,2-dimethyloxazolidine;

5-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-isopropyloxazolidine;and

5-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-t-butyl-2,2-dimethyloxazolidine.

The preferred pharmaceutically acceptable salts are hydrogen additionsalts of chloride, bromide, sulfate, maleate, lactate, tartrate,succinate and especially chloride and maleate. Thus, the preferred saltsare the preferred anion addition salts of formula II and III andcorrespondingly the particularly preferred salts are the preferredhydrogen-anion addition salts of the preferred and particularlypreferred compounds of formulas II and III and especially thehydrochloride and maleate salts.

The compounds of formula II can be prepared by applying the proceduresdescribed in U.S. Pat. No. 3,891,441 (e.g. Col. 16, line 20-Col. 20,line 46 and Col. 27, line 34-Col. 30, line 39), which procedures arehereby incorporated by reference, to the corresponding 5-positionsubstituted -2-bromo or -2-chloro thiazole substrate. These substratescan be prepared by applying the procedures described in Preparation 3,hereinbelow, to 2-bromo-5-carboxythiazole or 2-chloro-5-carboxythiazole.

The compounds of formula II can also be conveniently prepared byapplying the simplified procedure described by Berkoz, Lewis andMuchowski in U.S. application Ser. No. 706,412, filed on even dateherewith, to prepare the epoxy intermediate (B) and reacting thisintermediate in accordance with the present invention with theappropriate alkylamine to obtain the desired compound of formula II.This procedure can be schematically represented by the following overallreaction sequence: ##STR8## wherein X is chloro, bromo, --SOR⁶ or SO₂R⁶, wherein R⁶ is methyl, ethyl or benzyl; and Z and R² are as definedhereinabove.

Procedure (a) can be effected by treating the compound of formula a withglycidol anion in an inert organic solvent. This treatment isconveniently conducted by first treating glycidol with an alkali metalhydride to generate the glycidol anion. This initial treatment istypically conducted at temperatures in the range of about from -30° to30° C, preferably about from -10° to 5° C for about from 1 minute to 1hour, preferably about from 5 minutes to 20 minutes. The compound offormula A, typically dissolved in an inert organic solvent, can then betreated with the preceding glycidol anion mixture. Typically, thistreatment is conducted at temperatures in the range of about from -30°to 25° C, preferably about from -10° to 0° C, for about from 1 minute to1 hour, preferably about from 10 to 30 minutes. Typically, mole ratiosof alkali metal hydride to glycidol of about from 1 to 5 are used,preferably about from 1.0 to 1.3 , and mole ratios of compound offormula A to glycidol in the range of about from 1 to 5, preferablyabout from 1.0 to 1.3 are used. Suitable alkali metal hydrides which canbe used include, for example, sodium hydride, potassium hydride, lithiumhydride, and the like. Suitable inert organic solvents which can be usedinclude, for example, tetrahydrofuran, diethyl ether, dioxane,dimethoxyethane, dimethylformamdide and the like, and mixtures thereof.Both procedures of the treatment are conducted under anhydrousconditions, and preferably under an inert atmosphere (e.g. nitrogen).The resulting product of formula B is preferably isolated before beingused as starting material for the next step. Such isolation can beeffected by conventional separation procedures such as, for example,precipitation with water, extraction, crystallization, orchromatography. Specific illustrations of typical separation andisolation procedures can be had by reference to the appropiatepreparation, set forth hereinbelow.

The compounds of formula II can be conveniently prepared by treating thecompound of formula B with a monoalkylamine having the desired alkylsubstituent. Typically, this treatment is conducted in an inert organicsolvent and is typically conducted at temperature in the range of aboutfrom -10° to 100° C, preferably about from 10° to 25° C, for about from1 hour to 48 hours, preferably about from 5 to 18 hours. Typically, amole ratio of alkylamine to compound of formula B in the range of aboutfrom 1 to 30, preferably about from 1 to 10 is used. Suitablealkylamines which can be used include, for example, methylamine,ethylamine, isopropylamine, t-butylamine, n-pentylamine,4-methylpentylamine, and the like. Suitable inert organic solvents whichcan be used include, for example, methanol, ethanol, monoglyme, acetoneand the like and mixtures thereof. The resulting products of formula IIcan then be separated and isolated according to conventional proceduressuch as, for example, evaporation, crystallization, chromatography,thin-layer chromatography, etc. Specific illustrations of typicalseparation and isolation procedures can be had by reference to thecorresponding examples, set forth hereinbelow.

The X is --SOR⁶ and --SO₂ R⁶ starting materials of formula A can beprepared via the procedures described in Preparations A, B and 1-5 setforth hereinbelow or by obvious modifications thereof (for example,substitution of appropriate reagent such as, for example, methylmercaptan or benzyl mercaptan for ethane thiol (i.e. ethyl mercaptan) inPreparation 1.

The compounds of formula III can be prepared by applying the proceduresdescribed in U.S. Pat. No. 3,897,441 , Col. 28, line 18-Col. 29, line54, which procedures are hereby incorporated by reference, to theappropriate 2-bromo or ##STR9## thiazole. As before noted, theappropriate 2-bromo or 2-chloro substrates can be prepared by applyingthe procedures described in Preparation 3, hereinbelow, to 2-bromo or2-5-carboxythiazole.

The compounds of formula III can also be prepared directly from thecorresponding compounds of formula II: ##STR10## wherein R², R³ and Zare as defined hereinabove.

This treatment can be convenienty effected by treating the correspondingcompound of formula II with a ketone or aldehyde having the desired R⁴and R⁵ substituents. Where a ketone is used, the reaction can beeffected by treating the compound of formula II with the desired ketoneand aluminum isopropoxide or aluminum t-butoxide. Typically a mole ratioof about from 1 to 10 moles of aluminum isopropoxide or aluminumt-butoxide and a substantial excess of ketone (e.g. 2 to 150 moles)which serves as solvent, are used per mole of compound of formula II.Where an aldehyde is used the reaction can be effected by simplytreating the compound of formula II with the desired aldehyde using alower alkanol (e.g. ethanol) as solvent. Typically a mole ratio of aboutfrom 1 to 10 moles of aldehyde is used per mole of formula II. In bothcases the reaction are typically conducted at temperatures in the rangeof about from 20° to 100° C for about from 1 to 48 hours. Suitableketones and aldehydes which can be used include, for example,formaldehyde, acetaldehyde, benzaldehyde, acetone, diethylketone, andthe like.

The compounds of formula III can also be prepared via the proceduredescribed in the said application Ser. No. 706,412 filed on even dateherewith, and schematically represented hereinbelow. ##STR11## whereinR³, R⁴, R⁵, and Z are as defined hereinabove, and X' is --SOR⁶ or --SO₂R⁶ wherein R⁶ is methyl, ethyl or benzyl.

This procedure is preferably conducted in two steps. In the initial stepthe 5-hydroxymethyl-3-lower alkyl-oxazolidine or 2-mono or 2,2-dialkylderivative thereof (formula C) is treated with an alkaline metalhydride, e.g. sodium hydride, in a suitable inert organic solvent.Typically, this treatment is conducted at temperatures in the range ofabout from -5° to 100° C, preferably about from 25° to 60° C, for aboutfrom 10 minutes to 6 hours, preferably about from 1 to 3 hours. Suitableinert organic solvents which can be used include, for example,tetrahydrofuran, dimethylformamide, monoglyme, diglyme, and the like.The second step can be effected by treating the initial product reactionmixture with the desired 5-substituted-2-SOR⁶ or 2--SO₂ R⁶ thiazole.Typically, this treatment is conducted at temperature in the range ofabout from -20° to 80° C, preferably about from 0° to 30° C, for aboutfrom 1 minute to 10 hours, preferably about from 5 minutes to 2 hours.Typically, the thiazole reagent is added to the reaction mixture in theform of a solution in a suitable inert organic solvent. Suitable inertorganic solvents which can be used include, for example,tetrahydrofuran, dimethylformamide, monoglyme, diglyme, and the like.Also, in some instances, an excess of the oxazolidine reagent can beused as the solvent. Both steps of this procedure are conducted underanhydrous conditions and preferably are conducted under an inert gassuch as, for example, nitrogen.

The product of formula III can then be separated and purified accordingto conventional procedures such as, for example, illustrated in Example6, hereinbelow. Care should be exercised during the purificationprocedure as the compounds of formula III are easily hydrolyzed to thecompound of formula II under both acid and basic conditions.Correspondingly, the alkylamino compounds of formula II can be readilyprepared by simple acid or base hydrolysis of the correspondingcompounds of formula III. Acid hydrolysis can be conveniently effectedby treating the compound of formula III with a suitable organic acidsuch as, for example, acetic, formic, oxalic acid and the like orsuitable inorganic acid such as, for example, hydrochloric, sulfuric,and the like. Preferably this hydrolysis is conducted under mildlyacidic conditions. Similarly, basic hydrolysis can be conducted bytreating the compound of formula III with a suitable base such as, forexample, dilute sodium hydroxide, potassium hydroxide and the like.Preferably this hydrolysis is conducted under mildly alkalineconditions. Alternatively, the hydrolysis can be conducted via exchangewith a suitable ion exchange resin in either the H⁺ or OH⁻ form.

Where desired the individual diastereomeric and optical isomers can beobtained; (1) by conventional separation and purification procedures inthe case of diastereomeric isomers, and (2) via conventional resolutionprocedures in the case of optical isomers (for example, by reacting theoptical isomer mixtures with an optically active acid which will yield amixture of optical salts of the compounds of formula II which can beresolved by conventional procedures (e.g. crystallization) into therespective (+) and (-) optical salts. Optimum physical, orphysical-chemical, separation procedures and resolution procedures canbe obtained by routine trial and error procedures well within the scopeof those skilled in the art. The specific optical isomers, or, in someinstances, enriched optical isomer mixture, with respect to thepropan-2-ol side chain (formula II) can also be prepared by applying thecorresponding (+) or (-) optically active isomer of glycerol acetonidein the procedures referenced to U.S. Pat. No. 3,897,441, hereinabove onpage 11, to a 2-bromo, 2-chloro, 2-ethylsulfinyl or 2-ethylsulfonyl5-substituted thiazole starting material having the desired 5-positionsubstituent. Where enriched isomer mixtures are obtained, the respectiveoptical isomers can then be obtained by conventional resolutionprocedures.

The pharmaceutically acceptable acid addition salts of the compounds offormulas II and III can be prepared from the parent compound, viacareful neutralization of the 1-alkylaminopropane moiety, with thedesired acid. Other pharmaceutically acceptable addition salts can thenbe conveniently prepared from the addition salts via anion exchange witha suitable ion exchange resin in the desired anionic form.

The compounds, of the invention, are useful in the treatment andpalliation of cardiovascular abnormalities in mammals. These compoundsprimarily achieve their therapeutic action by selectively blocking thecardiac β-adreneric receptor sites and, accordingly, because they arecardiac selective, they can also be applied to treat cardiacabnormalities in patients suffering from asthma or chronic obstructivelung disease. Further, based on the virtual identity of therapeuticactivity, observed between the counterparts of formulas II and III, andthe fact that the compounds of formula III are readily hydrolyzed to thecompounds of formula II, it is believed that the compounds of formulaIII hydrolyze in vivo and hence function therapeutically as thecompounds of formula II. The compounds are especially useful in thetreatment or palliation of cardiac arrhythmias, angina pectoris,hypertrophic subaortic stenosis, pheochromocytoma, thyrotoxicosis,hyperkinetic syndromes, tetralogy of Fallot, mitral stenosis withtachycardia, general ischemic conditions, and hypertension founded onelevated cardiac outputs due to a hyperadrenergic state. The compoundsare active, both in the treatment or palliation of acute attacks of suchcardiac disorders, and further can be applied prophylactically toprevent or reduce the frequency of such attacks. This prophylacticaction is particularly desirable in reducing the frequency of attacks ofangina pectoris, since the medication (i.e. nitroglycerin) presentlycommonly used in the treatment of angina pectoris has no recognizedprophylactic action. Additional information concerning the use, actionand determination of β-blockers can be obtained by reference to theliterature such as, for example, Dotlery, et al., Clinical Pharmacologyand Therapeutics, volume 10, no. 6,765-797 and the references citedherein.

The compounds of the invention are also useful in the treatment ofhypertension in mammals.

The compounds of this invention are typically administered, both for thetreatment of cardiac disorders and hypertension, in dosages of aboutfrom 0.01 to 5 mg. per kg. of body weight. The precise effective dosagewill, of course, vary depending upon the mode of administration, thecondition being treated and the host. Where the compounds are used totreat cardiac conditions such as arrhythmias, the compounds aretypically administered either orally or intravenously. Where thecompounds are administered to treat hypertension or cardiac conditionssuch as angina pectoris, the compounds are, for the sake of convenience,typically administered orally.

The compounds of the invention can be administered for the treatment ofcardiac disorders and hypertension in a wide variety of dosage forms,either alone or in combination with other pharmaceutically compatiblemedicaments, in the form of pharmaceutical compositions suited for oralor parenteral administration. The compounds are typically administeredas pharmaceutical compositions consisting essentially of the compoundsof the invention and a pharmaceutical carrier. In the case of thecompounds of formula II, the compounds are typically administered aspharmaceutically acceptable salts. The pharmaceutical carrier can beeither a solid material or liquid, in which the compound is dissolved,dispersed or suspended, and can optionally contain small amounts ofpreservations and/or pH-buffering agents. Suitable preservatives whichcan be used include, for example, benzyl alcohol and the like. Suitablebuffering agents include, for example, sodium acetate and pharmaceuticalphosphate salts and the like.

The liquid compositions can, for example, be in the form of solutions,emulsions, suspensions, syrups or elixirs and optionally can containsmall quantities of preservatives and/or buffering agents, andpreferably contain the therapeutic agent in convenient unit dosageconcentrations.

The solid compositions can take the form of tablets, powders, capsules,pills or the like, preferably in unit dosage forms for simpleadministration or precise dosages. Suitable solid carriers include, forexample, pharmaceutical grades of starch, lactose, sodium saccharin,sodium bisulfite and the like.

Also based on studies on related compounds, it can be predicted that anumber of the present compounds will exhibit useful local anestheticactivity. Where the compounds are applied as local anesthetics, they canbe administered topically; intradermally; or subcutaneously.

A further understanding of the invention can be held from the followingnon-limiting Preparations and Examples. Also as used hereinabove andbelow unless expressly stated to the contrary, all temperatures andtemperature ranges refer to the Centrigrade system and the terms ambientor room temperature refer to about 20° C. The term percent or (%) refersto weight percent and the term mole or moles refers to gram moles. Theterm equivalent refers to a quantity of reagent equal in moles to themoles of the preceding or succeeding reactant recited in thatPreparation or Example in terms of moles or finite weight or volume.Also unless expressly stated to the contrary, recemic mixtures and/ordiastereomer mixtures are used as starting materials and correspondinglyracemic mixtures and/or diastereomer mixtures are obtained as productsand where necessary, preparations and examples are repeated to providesufficient quantities of starting materials for subsequent preparationsand examples.

PREPARATION A Alkynylamines

a. In this preparation 1.0 mole of p-toluenesulfonyl chloride isdissolved in 700 ml. of pyridine at 0° C, under nitrogen, and then 0.5mole of hex-5-yn-1-ol is added dropwise. The mixture is stirred for 2hours and then 10 ml. of water is added slowly, keeping the temperaturebelow 10° C. The pyridine is then removed by evaporation under vacuumand the residue poured into 1 liter of ethyl acetate, then washed twicewith excess 2N aqueous hydrochloric acid, and then with water. Theorganic layer is separated and dried over anhydrous magnesium sulfate,filtered, and the filtrate then evaporated to dryness, under vacuum,affording hex-5-yn-1-ol tosylate.

b. A mixture containing 0.397 mole of hex-5-yn-1-ol tosylate; 0.76 moleof sodium azide; and one liter of methanol and 200 ml. of water isstirred at 60° C for 4 hours. The mixture is then evaporated undervacuum to remove the majority of the methanol and the remainingconcentrate then poured into 500 ml. of ethyl ether, and then extractedthree times with water, and dried over anhydrous magnesium sulfate andfiltered. The filtrate is then evaporated, under vacuum, affording1-azidohex-5-yne as a residue.

c. 0.122 Mole of lithium aluminum hydride is dissolved in 500 ml. ofethyl ether, under nitrogen, and then 0.244 mole of 1-azidohex-5-yne in100 ml. of diethyl ether is added dropwise. The mixture is then stirredat room temperature for 4 hours and then cooled to 0° C and 10 ml. ofwater carefully added and the mixture then filtered. The filtrate isthen dried over potassium hydroxide pellets, filtered, and the filtratedistilled, affording 1-aminohex-5-yne as a residue.

Similarly, by following the same procedure as described above, but usingthe corresponding alkynyl-ols as starting materials in place ofhex-5-yn-1-ol, in paragraph (a), the following alkynylamines arerespectively prepared.

1-aminobut-3-yne;

1-aminopent-3-yne;

1-aminohex-3-yne;

1-aminohept-3-yne;

1-amino-5-methylhex-3-yne;

1-aminooct-2-yne;

1-amino-6-methylhept-3-yne;

1-aminopent-4-yne;

1-aminohex-4-yne;

1-aminohept-4-yne;

1-aminooct-4-yne;

1-amino-6-methylhept-4-yne;

1-aminohept-5-yne; and

1-aminooct-5-yne.

PREPARATION B Alkynylamines

a. This preparation illustrates further procedures for preparingalkynylamines. In this preparation 0.1 mole of 5,5-dimethylhex-3-yn-1-olis mixed with 0.1 mole of triphenylphosphine in 40 ml. of carbontetrachloride and then heated, under nitrogen, at 60° C for 4 hours. Themixture is then poured into 200 ml. of hexane, stirred, and thenfiltered and the filtrate concentrated by evaporation under vacuum. Theconcentrate is then chromatographed on silica gel eluting with 5% ethylacetate-95% vol. hexane, affording 5,5-dimethylhex-3-yn-1-yl chloride.b. 0.069 Mole of 5,5-dimethylhex-3-yn-1-yl chloride is treated accordingto the procedures described in paragraph (b) of Preparation A, affording1-azido-5,5-dimethylhex-3-yne. c. 0.069 Mole of1-azido-5,5-dimethylhex-3-yne is treated according to the proceduredescribed herein in paragraph (c) of Preparation A affording1-amino-5,5-dimethylhex-3-yne.

Similarly by following the same procedure as described hereinabove byusing the corresponding alkynyl-1-ol starting materials, thealkynylamines, prepared in Preparation A, are respectively prepared.

PREPARATION 1 2-Ethylthiothiazole

In this preparation 0.15 moles of 50% sodium hydride in mineral oil isstirred in 100 ml. of dimethylformamide, under a nitrogen atmosphere,then cooled to -50° C and 0.15 moles of ethanethiol is added dropwise.The resulting mixture is warmed to 0° C and then recooled to -50° C and0.1 moles of 2-bromothiazole (K. Ganapthi et al., Proc. Indian Acad.Sci., A22, 362 (1945) is added. The resulting mixture is warmed to roomtemperature (about 20° C) and maintained at this temperature until thereaction is determined to be complete as shown by thin-layerchromatography; about two hours. The mixture is then poured into 500 ml.of hexane, then washed three times with water. The organic layer isdried with anhydrous magnesium sulfate, filtered, and the resultingfiltrate evaporated under vacuum yielding 2-ethylthiothiazole as acolorless oil.

PREPARATION 2 2-Ethylthio-5-carboxythiazole

In this preparation 0.2 moles of 2-ethylthiothiazole is dissolved in 300ml. of anhydrous tetrahydrofuran, under a nitrogen atmosphere, thencooled to -80° C. 0.2 Moles of butyl lithium in 125 ml. of hexane isthen added dropwise with stirring. The mixture is stirred for 5 minutesand then anhydrous carbon dioxide bubbled through the mixture untilreaction is completed (the reaction is monitored by thin-layerchromatography). The mixture is allowed to warm to 0° C, 300 ml. ofhexane added, and then filtered. The filter cake is recovered and washedwith ethyl ether, affording the lithium salt of2-ethylthio-5-carboxythiazole, and then slurried with 300 ml. of ethylacetate. The ethyl acetate slurry is then acidified with 2 Normalhydrochloric acid and washed with water. The organic layer is recovered,dried with anhydrous magnesium sulfate, and the resulting filtrateevaporated to dryness under vacuum yielding2-ethylthio-5-carboxythiazole.

PREPARATION 3 2-Alkylthio-5-alkynylaminocarbonylthiazole

In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole isdissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and0.1 moles of triethylamine is added and the resulting mixture cooled to-30° C. 0.1 Mole of ethylchloroformate is then added dropwise withstirring and the resulting mixture allowed to warm to 0° C. The mixtureis then stirred for ten minutes, then cooled to -30° C and 0.11 mole of1-aminohex-5-yne in 50 ml. of tetrahydrofuran added dropwise. Themixture is allowed to warm to room temperature (about 20° C), pouredinto 500 ml. of ethyl acetate, washed with water, then washed withsaturated aqueous sodium chloride solution, and dried over magnesiumsulfate. The mixture is then filtered and the solvent from the resultingfiltrate is evaporated under vacuum yielding2-ethylthio-5-(hex-5-ynylaminocarbonyl)thiazole as a solid, which isthen further purified by recrystallization from ethyl acetate.

Similarly, by following the same procedure but respectively using thecorresponding aminoalkyne products of Preparations A and B hereinabove,in place of 1-aminohex-5-yne, the following compounds are respectivelyprepared:

2-ethylthio-5-(but-3-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(pent-3-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(hex-3-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(hept-3-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(5-methylhex-3-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(5,5-dimethylhex-3-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(pent-4-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(hex-4-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(hept-4-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(oct-4-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(6-methylhept-4-ynylaminocarbonyl)thiazole;

2-ethylthio-5-(hept-5-ynylaminocarbonyl)thiazole; and

2-ethylthio-5-(oct-5-ynylaminocarbonyl)thiazole.

PREPARATION 4 2-Ethylsulfinyl-5-alkynylaminocarbonylthiazole

In this preparation a mixture of 0.064 mole of2-ethylthio-5-(hex-5-ynylaminocarbonyl) thiazole; 40 ml. of 30% aqueoushydrogen peroxide and 200 ml. of acetic acid is stirred at a temperatureof from 40° to 50° C for 4 hours. The mixture is concentrated byevaporation of a large portion of the acetic acid, under vacuum, at roomtemperature (about 20° C) and the resulting residue poured into 500 ml.of ethyl acetate and then washed with aqueous sodium bicarbonatesolution until no acetic acid is present in the organic layer. The ethylacetate layer is then separated, dried with anhydrous magnesium sulfate,filtered, and the resulting filtrate evaporated to dryness, undervacuum, affording 2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole.

Similarly, by following the same procedure but respectively replacing2-ethylthio-5-(hex-5-ynylaminocarbonyl)thiazole with the products ofPreparation 3, the corresponding 2-ethylsulfinyl analogs arerespectively prepared.

PREPARATION 5 2-Ethylsulfonyl-5-alkynylaminocarbonylthiazole

In this preparation a mixture of 0.028 mole of2-ethylthio-5-(5-methylhex-3-ynylaminocarbonyl)thiazole; 20 ml. of 30%hydrogen peroxide and 100 ml. of acetic acid are heated at 55° C for 16hours, most of the acetic acid is then removed by evaporation undervacuum and the resulting residue dissolved in 250 ml. of ethyl acetateand then washed with aqueous sodium bicarbonate solution until alltraces of acetic acid are removed. The ethyl acetate layer is separatedand then dried with anhydrous magnesium sulfate, filtered, and theresulting filtrate evaporated under vacuum to dryness affording2-ethylsulfonyl-5-(5-methylhex-3-ynylaminocarbonyl)thiazole.

Similarly, by following the same procedure but respectively replacing2-ethylthio-5-(5-methylhex-3-ynylaminocarbonyl)thiazol with the productsof Preparation 3, the corresponding 2-ethylsulfonyl analogs arerespectively prepared.

PREPARATION 6 1,2Epoxy-3-(5-alkynylaminocarbonylthiazol-2-yloxy) propane

In this preparation 0.0525 mole of sodium hydride in a 50% mineral oilmixture is stirred in 300 ml. of anhydrous tetrahydrofuran, undernitrogen, then cooled to -30° C and 0.055 mole glycidol is addeddropwise. The mixture is allowed to warm -5° C and stirred for 10minutes and then recooled to -30° C. A solution of 0.05 mole of2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole in 100 ml. ofanhydrous tetradrofuran is added dropwise and the resulting solvent isadded as needed to facilitate stirring. The mixture is maintained for 30minutes at 0° C and then poured into 500 ml. of ethyl acetate, extractedwith 100 ml. of water, and then with 100 ml. of aqueous saturated sodiumchloride and dried over anhydrous magnesium sulfate and filtered. Thefiltrate is evaporated under vacuum affording an oily residue which isthen further purified by chromatography on silica gel eluting with 40%ethyl acetate-60% hexane, by vol., affording1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane.

Similarly, by following the same procedure, the products of Preparation4 are respectively converted into the corresponding 1,2-epoxy analogs.

PREPARATION 7 1,2-Epoxy-3-(5-alkynylaminocarbonylthiazol-2-yloxy)propane

In this preparation 0.0525 mole of sodium hydride in a 50% mineral oilmixture is stirred in 300 ml. of anhydrous tetrahydrofuran, undernitrogen, then cooled to -30° C and 0.055 mole of glycidol is addeddropwise. The mixture is allowed to warm to -5° C and stirred for 10minutes and then recooled to -30° C. A solution of 0.05 mole of2-ethylsulfonyl-5-(5-methylhex-3-ynylaminocarbonyl)thiazole in 100 ml.of anhydrous tetrahydrofuran is added dropwise and the resulting mixtureallowed to warm to 0° C. Additional solvent is added as needed tofacilitate stirring. The mixture is maintained at 30 minutes at 0° C andthen poured into 500 ml. of ethyl acetate, extracted with 100 ml. ofwater, and then with 100 ml. of aqueous saturated sodium chloride anddried over anhydrous magnesium sulfate and filtered. The filtrate isevaporated under vacuum affording an oily residue which is then furtherpurified by chromatography on silica gel eluting with 40% ethylacetate-60% hexane, by vol., affording1,2-epoxy-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]propane.

Similarly, by following the same procedure, the products of Preparation5 are respectively converted into the corresponding 1,2-epoxy analogs.

PREPARATION 8

In this example sodium hydride (18 g., 56 wt. % dispersion in oil) iswashed with n-hexane, and the hexane is replaced with monoglyme (100ml.). To this mixture is added a solution of 44.5 g. of (+) glycerolacetonide (J. Biol. Chem., v. 128, page 463 (1939) in monoglyme (200ml.) under an atmosphere of nitrogen. After 15 minutes,2-ethylsulfonyl-5-(hex-5-ynylaminocarbonyl)thiazole (32 g.) is added,and the mixture is refluxed for 1 hour. The reaction mixture is thencooled, diluted with ethyl ether, washed with saturated aqueous sodiumchloride solution twice, dried and concentrated by evaporation. Columnchromatography, eluting with ethyl acetate/hexane (1:1), yields (+)3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propanediol 1,2-acetonide.

Similarly, by following the same procedure but respectively replacing2-ethylsulfonyl-5-(hex-5-ynylaminocarbonyl) thiazole with the compoundsprepared in Preparations 4 and 5, the corresponding (+)3-(5-alkynylaminocarbonylthiazol-2-yloxy)-propanediol 1,2-acetonidecompounds are respectively prepared.

Similarly, the above procedure is respectively repeated with each of theabove 2-ethylsulfinyl and 2-ethylsulfonyl starting materials but using(-) glycerol acetonide (J. Am. Chem. Soc., v. 67, page 944 (1945)) inplace of (+) glycerol acetonide to yield the corresponding (-)3-(5-alkynylaminocarbonylthiazol-2-yloxy)propanediol 1,2-acetonide.

PREPARATION 9

In this example a mixture containing 2 g. of (+)3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propanediol 1,2-acetonidein 25 ml. of 80% aqueous formic acid is stirred at room temperature for5 minutes. The solution is then evaporated under vacuum at roomtemperature affording a residue of (+)3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane-1,2-diol which isthen further purified by recrystallization using an ethyl acetate-hexanemixture.

Similarly, by following the same procedure, the products preparedaccording to Preparation 8 are respectively cleaved to the correspondingoptically active propanediol compounds.

PREPARATION 10

In this example 0.42 g. of methanesulfonyl chloride is added with rapidstirring to a mixture containing 1.2 g. of (+)3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane-1,2-diol in 20 ml.of pyridine at -30° C. The mixture is then allowed to warm to roomtemperature and evaporated to dryness affording a residue of (+)2-hydroxy-1-methylsulfonyloxy-3-(5(-hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane.The residue is then dissolved in 50 ml. of anhydrous methanol and cooledto 0° C. A mixture containing 1 g. of sodium methoxide in 10 ml. ofanhydrous methanol is added and the resulting mixture stirred for 2minutes and then evaporated to remove methanol. 100 Ml. of ethyl acetateis added and the resulting ethyl acetate mixture washed three times withwater, dried over magnesium sulfate, and evaporated affording a residueof (+) 1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane.

Similarly, by following the same procedure as above, the products ofPreparation 9 are respectively converted to the corresponding opticallyactive 1,2-epoxypropane-5-substituted alkylaminocarbonylthiazolederivatives.

EXAMPLE 1

This examole illustrates methods for preparing the compounds of thepresent invention. In this examole a mixture containing 12 g. (0.037mole) of1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane, 12 g.(0.164 mole) of t-butylamine and 20 ml. of ethanol is allowed to standat room temperature for 12 hours. The mixture is then evaporated undervacuum to remove the ethanol solvent and the resulting residue dissolvedin 50 ml. of ethyl acetate and cooled to -20° C, and maintained at thistemperature for two hours. The mixture is then filtered and theresulting filter cake washed with cold (about 0° C) ethyl ether and thenrecrystallized from ethyl acetate affording1-t-butylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propan-2-ol,m.p. 140°-148° C.

Similarly, by following the same procedure but using the correspondingproducts of Preparation 6 as starting materials, the following compoundsare respectively prepared.

1-t-butylamino-3-[5-(but-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(pent-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-2-ol, m.p.90°-91° C;

1-t-butylamino-3-[5-(hept-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(oct-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(6-methylhept-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(5,5-dimethylhex-3-ynylaminocarbonyl)-thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-pent-4-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(hex-4-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(hept-4-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(6-methylhept-4-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-t-butylamino-3-[5-(hept-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;and

1-t-butylamino-3-[5-oct-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.

Similarly, by following the same procedure but replacing t-butylaminewith methylamine and hexylamine, the corresponding methylamino andhexylamino homologs of the above products are respectively prepared.

Similarly, by following the same procedure but using the products ofPreparation 10 as starting materials, the corresponding (+) and (-)optically active (relative to the propan-2-ol side chain) isomers ofeach of the above products is respectively prepared.

EXAMPLE 2

This example illustrates methods for preparing the compounds of thepresent invention. In this example a mixture containing 12 g. (0.0314mole) of1,2-epoxy-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]propane,12 g. (0.203 mole) of isopropylamine and 20 ml. of ethanol is allowed tostand at room temperature for 12 hours. The mixture is then evaporatedunder vacuum to remove the solvent and the resulting residue dissolvedin 50 ml. of ethyl acetate and cooled to -20° C, and maintained at thistemperature for 2 hours. The mixture is then filtered and the resultingfilter cake washed with cold (about 0° C) ethyl ether and thenrecrystallized from ethyl acetate affording1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.

Similarly, by following the same procedure but using the correspondingproducts of Preparation 7 as starting materials, the following compoundsare respectively prepared:

1-ispropylamino-3-[5-(but-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(pent-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(hept-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(oct-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(6-methylhept-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(5,5-dimethylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-]5-(pent-4-ynylaminocarbonyl)thiazol--yloxy]-propan-2-ol;

1-isopropylamino-3-[5-hex-4-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(hept-4-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;

1-isopropylamino-3-]5(hept-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol;and

1-isopropylamino-3-[-(oct-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.

Similarly, by following the same procedure but replacing isopropylaminewith ethylamine and and pentylamine, the corresponding ethylamino andpentylamino homologs of the above products are respectively prepared.

Similarly, by following the same procedure but using the products ofPreparation 10 as starting materials, the corresponding (+) and (-)optically active (relative to the propan-2-ol side chain) isomers ofeach of the above products is respectively prepared.

EXAMPLE 3

This example illustrates methods of preparing hydrochloride additionsalts of the compounds of formula II. In this example 1 g. of1-t-butylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-olis dissolved in 10 ml. of ethyl ether at 20° C. A stream of gaseousanhydrous hydrogen chloride is passed over the surface of the solutionuntil the supernatent liquid becomes clear. The resulting precipitate iscollected by filtration, washed with ethyl ether and then crystallizedfrom methanol/diethyl ether, affording crystalline1-t-butylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol hydrochloride.

Similarly, by following the same procedure, the correspondinghydrochloride addition salts of each of the products of Examples 1 and 2are respectively prepared, for example:

1-isopropylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-olhydrochloride.

EXAMPLE 4

This example illustrates methods of preparing the maleate addition saltsof compounds of formula II. In this example 1 gram of1-t-butylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-olis dissolved in a solution of 5 ml. of ethyl ether and 5 ml. of ethanolat 20° C. To this solution is added 10 ml. of a saturated solution ofmaleic acid is ethyl ether. The mixture is allowed to stand for one hourat room temperature. The resulting precipitate is recovered byfiltration, washed three times with ethyl ether and then crystallizedfrom a mixture of ethyl ether and ethanol (1:1) affording crystalline1-t-butylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-olmaleate, m.p. 174°-175° C.

Similarly, by following the same procedure, the corresponding maleatesalts of each of the products of Examples 1 and 2 are respectivelyprepared, for example:

1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol maleate, m.p. 152°-153° C.

EXAMPLE 5

This example illustrates methods of converting the corresponding R²compounds of formula II into the corresponding compounds of formula IIIof the invention. In this example, 1 g. of1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-olis dissolved in 25 ml. of acetone at 20° C, and 2 g. of aluminumisopropoxide is then added. The solution is stirred for 4 days at 20° Cand then 50 ml. of ethyl ether and 5 ml. of water are added and theresulting mixture is allowed to stand for 15 minutes. The resultingethyl ether phase is separated and then evaporated to dryness yielding5-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-isopropyl-2,2-dimethyloxazolidine.

Similarly, by following the same procedure, products of Examples 1 and 2are respectively converted into the corresponding compounds of formulaIII.

EXAMPLE 6

This examples illustrates the preparation of the compounds of formulaIII, via the procedure described in the Application of Berkoz, Lewis andMuchowski, Ser. No. 706,412, filed on even date herewith. In thisexample 0.012 mole of sodium hydride (50% mineral oil) is stirred in 50ml. of tetrahydrofuran; under nitrogen, and 0.02 mole of5-hydroxymethyl-N-t-butyloxazolidine is added. The mixture is thenwarmed to 50° C until reaction ceases (about 30 minutes) and then cooledto room temperature. 0.01 Mole of2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole in 50 ml. oftetrahydrofuran is then added. The mixture is stirred for 4 hours atroom temperature and then poured into 200 ml. of ethyl acetate, thenwashed with water; dried over anhydrous magnesium sulfate and filtered.The filtrate is evaporated under vacuum affording a crude5-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-t-butyloxazolidineresidue which is then dissolved in 100 ml. of diethyl ether and thenhydrochloric acid gas is passed over the surface with rapid stirringuntil no more precipitate is formed. The precipitate is filtered off,washed with diethyl ether, and then recrystallized from a mixture ofpropanol and diethyl ether. The crystals are collected by filtration anddried under vacuum affording5-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-t-butyloxazolidinehydrochloride.

Similarly, by following the same procedure but using the products ofPreparation 4 as starting materials, the corresponding compounds offormula III and their hydrochloride salts are respectively prepared.

Similarly, by following the same procedure but respectively using the2-ethylsulfonyl products of Preparation 5 as starting materials, thecorresponding compounds of formula III and their hydrochloride salts arerespectively prepared.

EXAMPLE 7

This example illustrates methods of converting the compounds of formulaIII into the compounds of formula II of the invention. In this example 1g. of5[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-t-butyl-2,2-dimethyloxazolidineis dissolved in 50 ml. of tetrahydrofuran and this solution is treatedwith aqueous 5% sodium hydroxide (20 ml.) at 20° C. The mixture isstirred for 0.5 hour, extracted three times with methylene chloride,washed with water, dried over magnesium sulfate and then evaporated todryness affording1-t-butyl-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.

Similarly, by following the same procedure, the products of Example 6are respectively hydrolyzed to the corresponding compounds of formulaII.

EXAMPLE 8

This example illustrates an alternate method for converting thecompounds of formula III to the compounds of formula II. In this example1 g. of5-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-t-butyloxazolidineis dissolved in 20 ml. of methanol containing 4 cc. of 5% aqueoushydrochloric acid at 20° C. After 15 minutes, the mixture is neutralizedwith dilute aqueous sodium carbonate solution, poured into water andextracted with ethyl acetate. The ethyl acetate extract is evaporated todryness yielding1-t-butylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.

Similarly, by following the same procedure, the products of Example 6are respectively hydrolyzed to the corresponding compounds of formulaII.

EXAMPLE 9

This example illustrates further methods of converting the compounds offormula II into the corresponding compounds of formula III. In thisexample 1 m. mole of1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-olin 10 ml. of methanol is admixed with 20 ml. of 37% aqueous formaldehydeand then stirred at room temperature for 1 hour. The solvent is thenremoved by evaporation under vacuum affording a crude5-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-isopropyloxazolidineresidue which is then stirred in 50 ml. of ethyl ether and filtered.Gaseous hydrogen chloride is passed over the surface of the filtratewith rapid stirring until no further precipitate is formed. Theprecipitate is filtered off, washed with diethyl ether and thenrecrystallized from a mixture of propanol and diethyl ether affording5-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-methylene-N-isopropyloxazolidinehydrochloride.

Similarly, by following the same procedure, the products of Examples 1and 2 are respectively converted to the corresponding compounds offormula III and their hydrochloride salts.

Similarly by following the same procedure but using acetaldehyde inplace of formaldehyde, the corresponding 2-methyloxazolidine homologs ofthe above products are respectively prepared.

Obviously many modifications and variations of the invention, describedherein above and below in the Claims, can be made without departing fromthe essence and scope thereof.

What is claimed is:
 1. A compound selected from the group having theformula: ##STR12## wherein Z has the formula:

    R.sup.1 --C.tbd.C--(CH.sub.2).sub.n --

wherein n is 2, 3 or 4; R¹ is hydrogen or an alkyl group having from onethrough four carbon atoms; and wherein Z has from four through eightcarbon atoms; Y is selected from the group having the formulas:

    --CHOH--CH.sub.2 NHR.sup.2 ;

or ##STR13## wherein R² and R³ are lower alkyl and R⁴ and R⁵ areindependently selected from the group of hydrogen or lower alkyl; andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1selected from the group having the formula: ##STR14## wherein R² islower alkyl and Z has the formula

    R.sup.1 --C.tbd.C--(CH.sub.2).sub.n --

wherein n is 2, 3 or 4; R¹ is hydrogen or an alkyl group having from onethrough four carbon atoms and wherein Z has from four through eightcarbon atoms;and pharmaceutically acceptable salts thereof.
 3. Thecompound of claim 2 wherein n is
 2. 4. The compound of claim 2 whereinR² is selected from the group of isopropyl and t-butyl.
 5. The compoundof claim 2 wherein R² is isopropyl.
 6. The compound of claim 2 wherein nis 2 and R¹ is ethyl or isopropyl.
 7. The compound of claim 6 wherein R²is isopropyl or t-butyl.
 8. The compound of claim 7 wherein saidcompound is selected from the group consisting of1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxyl-propan-2-oland pharmaceutically acceptable salts thereof.
 9. The compound of claim7 wherein said compound is selected from the group consisting of1-t-butylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-oland pharmaceutically acceptable salts thereof.
 10. The compound of claim7 wherein said compound is selected from the group consisting of1-isopropylamino-3-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-oland pharmaceutically acceptable salts thereof.
 11. The compound of claim7 wherein said compound is selected from the group consisting of1-t-butylamino-3-[5-(hex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-oland pharmaceutically acceptable salts thereof.
 12. The compound of claim2 wherein n is
 3. 13. The compound of claim 12 wherein R¹ is methyl orethyl.
 14. The compound of claim 12 wherein R² is isopropyl or t-butyl.15. The compound of claim 14 wherein R¹ is methyl.
 16. The compound ofclaim 14 wherein R¹ is ethyl.
 17. The compound of claim 2 wherein n is4.
 18. The compound of claim 17 wherein R¹ is hydrogen or methyl. 19.The compound of claim 17 wherein R² is isopropyl or t-butyl.
 20. Thecompound of claim 19 wherein R¹ is hydrogen.
 21. The compound of claim19 wherein R¹ is methyl.
 22. The compound of claim 1 selected from thegroup having the formula: ##STR15## wherein n is 2, 3 or 4; Z has theformula:

    R.sup.1 --C.tbd.C--(CH.sub.2).sub.n --

wherein R¹ is hydrogen or an alkyl group having from one through fourcarbon atoms and wherein Z has from four through eight carbon atoms: R³is lower alkyl; and R⁴ and R⁵ are independently selected from the groupof hydrogen and lower alkyl;and pharmaceutically acceptable saltsthereof.
 23. The compound of claim 22 wherein n is
 2. 24. The compoundof claim 22 wherein R⁴ and R⁵ are independently selected from the groupof hydrogen and methyl.
 25. The compound of claim 22 wherein n is 2; R¹is ethyl or isopropyl and R³ is isopropyl or t-butyl.
 26. The compoundof claim 25 wherein R⁴ and R⁵ are each hydrogen or are each methyl. 27.The compound of claim 22 wherein n is 3, R¹ is methyl or ethyl, and R³is isopropyl or t-butyl.
 28. The compound of claim 27 wherein R⁴ and R⁵are each hydrogen or are each methyl.
 29. The compound of claim 22wherein n is 4, R¹ is hydrogen or methyl and R³ is isopropyl or t-butyl.30. The compound of claim 29 wherein R⁴ and R⁵ are each hydrogen or areeach methyl.
 31. The compound of claim 2 wherein when said compound is apharmaceutically acceptable salt said salt is selected from the groupconsisting of hydrochloride and maleate salts.
 32. The compound of claim8 wherein when said compound is a pharmaceutically acceptable salt saidsalt is selected from the group consisting of hydrochloride and maleatesalts.
 33. The compound of claim 9 wherein when said compound is apharmaceutically acceptable salt said salt is selected from the groupconsisting of hydrochloride and maleate salts.
 34. The compound of claim10 wherein when said compound is a pharmaceutically acceptable salt saidsalt is selected from the group consisting of hydrochloride and maleatesalts.
 35. The compound of claim 11 wherein when said compound is apharmaceutically acceptable salt said salt is selected from the groupconsisting of hydrochloride and maleate salts.
 36. The compound of claim22 wherein when said compound is a pharmaceutically acceptable salt saidsalt is selected from the group consisting of hydrochloride and maleatesalts.
 37. The compound of claim 34 wherein said compound is ahydrochloride salt.
 38. A pharmaceutical composition, for treatingcardiovascular disorders in mammals by blocking β-adrenergic receptorsites, consisting essentially of a pharmaceutically acceptable carrierand an amount effective to block β-adrenergic receptor sites on an agentselected from the group of the compounds of claim 1 and mixturesthereof.
 39. A pharmaceutical composition for treating cardiovasculardisorders in mammals by blocking β-adrenergic receptor sites, consistingessentially of a pharmaceutically acceptable carrier and an amounteffective to block β-adrenergic receptor sites of an agent selected fromthe group of the compounds of claim 2 and mixtures thereof.
 40. Apharmaceutical composition, for treating cardiovascular disorders inmammals by blocking β-adrenergic receptor sites, consisting essentiallyof a pharmaceutically acceptable carrier and an amount effective toblock β-adrenergic receptor sites of an agent selected from the group ofthe compounds of claim 22 and mixtures thereof.
 41. A pharmaceuticalcomposition for treating hypertension disorders in mammals consistingessentially of a pharmaceutically acceptable carrier and an amounteffective to treat hypertension of an agent selected from the group ofthe compounds of claim 1 and mixtures thereof.
 42. A pharmaceuticalcomposition for treating hypertension disorders in mammals consistingessentially of a pharmaceutically acceptable carrier and an amounteffective to treat hypertension of an agent selected from the group ofthe compounds of claim 2 and mixtures thereof.
 43. A pharmaceuticalcomposition for treating hypertension disorders in mammals consistingessentially of a pharmaceutically acceptable carrier and an amounteffective to treat hypertension of an agent selected from the group ofthe compounds of claim 22 and mixtures thereof.